Lower urinary tract disorders encompass an assortment of syndromes that affect normal micturition. Lower urinary tract disorders may develop through combination of pathological and/or age-related changes of the urogenital system, or other etiology, e.g., neurological disorders. Individuals suffering from lower urinary tract disorders suffer from impaired quality of life, including embarrassment, poor self-perception, and a general reduction in emotional well-being, social function, and general health. Lower urinary tract disorders, moreover, may be associated with other physical ailments, including cellulitis, pressure ulcers, urinary tract infections, falls with fractures, sleep deprivation, social withdrawal, depression, and sexual dysfunction. Older individuals suffering from lower urinary tract disorders may require more care from health care providers, both family and professional, which may be a factor in decisions to place them in institutions.
According to the U.S. National Institutes of Health (NIH), up to 35 million Americans are estimated to suffer from lower urinary tract disorders. Lower urinary tract disorders are more common among women than men (2:1) until age 80, after which men and women are equally affected. The prevalence of lower urinary tract disorders increases with age. By the age 65, lower urinary tract disorders affect 15% to 30% of all individuals and approximately 50% of individuals in long-term care.
Agents with various modes of action have been used to treat lower urinary tract disorders. These include agents that act directly on the lower urinary tract, e.g., antimuscarinics and alpha-1 antagonists, and agents that act through the central nervous system, e.g., serotonin and/or noradrenaline reuptake inhibitors. According to the NIH, however, while some progress has been made in the diagnosis, management, and treatment of lower urinary tract disorders, these disorders frequently remain intractable. Thus, there is a continued need for improved agents, formulations and therapies to treat lower urinary tract disorders.
Glutamic acid, an excitatory amino acid, is present at synapses throughout the central nervous system and is known to act on at least two types of receptors: ionotropic and metabotropic glutamate receptors. The principle function of ionotropic glutamate receptors is that their activation forms ligand-gated ion channels and, thereby, they directly mediate electrical signaling of nerve cells, producing rapid and relatively large conductance changes in the post-synaptic membranes. Metabotropic glutamate receptors (mGluRs) regulate electrical signaling indirectly, by influencing intracellular metabolic processes via G-proteins. Changes in the post-synaptic cell that are mediated through mGluRs are consequently relatively slow over time and are not linked to rapid and large changes in neuronal membrane conductance.
Three subtypes of ionotropic glutamate receptors have been described, i.e., the NMDA, AMPA and kainate subtypes.
Eight subtypes of metabotropic glutamate receptors have been cloned. The subtypes are classified into three groups on the basis of sequence similarities, and pharmacological and biochemical properties (Spooren et al., Trends Pharmacol. Sci. 22: 331-337, 2001): Group I mGlu receptors (mGlu1 and mGlu5), Group II mGlu receptors (mGlu2 and mGlu3) and Group III mGlu receptors (mGlu4, mGlu6, mGlu7 and mGlu8).
Group I receptor mGlu5 (either human or rat) is known to comprise at least two subtypes, “a” and “b”. Subtype “b” is longer than subtype “a”, because of an alternative splicing of a 32-amino-acid stretch in the C-terminal (intracellular) domain, 50 residues downstream of the beginning of the domain. The human mGlu5b is 1212 amino acids long, while the “a” form lacks the amino acids from 877 to 908 (n. 828 being the first of the intracellular domain). The rat mGlu5b is 1203 amino acids long, while the “a” form lacks the amino acids from 876 to 907 (n. 827 being the first of the intracellular domain). (Hermans and Challis, Biochem. J. 359: 465-484, 2001).
The mGlu receptors, belonging to family 3 of GPCRs, are characterized by two distinct topological domains: a large extracellular N-terminal domain containing a Venus fly-trap module responsible for agonist binding and the 7-TM domain plus intracellular C-terminal domain that is involved in receptor activation and G-protein coupling.
The 7-TMD of mGlu Group I receptors has been shown to form a binding pocket for positive and negative allosteric modulators; the negative ones have been identified thanks to high throughput screening technologies and act as non-competitive antagonists, having no effect on agonist binding. The most interesting property of these molecules, in addition to their high potency, is their remarkable subtype selectivity.
The 7-TM binding region is located in a pocket-lined by TM-III, TM-V, TM-VI and TM-VII; this site corresponds to the retinal binding pocket in rhodopsin.
Allosteric modulators of mGlu5 represent an exciting advance in demonstrating the potential for developing novel research tools and therapeutic agents that regulate activity of specific mGluR subtypes.
The compounds of the instant invention include those reported herein as mGlu5 antagonists, which in many cases are actually negative allosteric modulators acting at the 7-TM binding region.
WO 00/63166 discloses tricyclic carbamic acid derivatives useful for the treatment of different diseases, including urinary incontinence. The derivatives are disclosed to be agonists or antagonists of Group I mGlu receptors with specificity for the mGlu1 receptor.
WO 01/32632 discloses pyrimidine derivatives useful for the treatment of different diseases, including urinary incontinence. The derivatives are disclosed as selective antagonists of the mGlu1 receptor with at least 10-fold selectivity for the mGlu1 receptor over the mGlu 5 receptor.
WO 01/27070 discloses new bisarylacetamides useful for the treatment of urinary incontinence, among other conditions. The molecules are disclosed to be agonists or antagonists selective for the mGlu1 receptor.
U.S. Pat. No. 6,369,222 discloses heterocycloazepinyl pyrimidine derivatives useful for the treatment of urinary incontinence, among other conditions. The derivatives are disclosed to be antagonists of the mGlu1 receptor.
The aforementioned applications and patent, therefore, disclose mGlu1 receptor antagonists as useful for treating urinary incontinence. None of the references, however, provide experimental support for treatment of urinary incontinence, either in human patients or in an animal model for lower urinary tract disease.
We have tested the activity of selective mGlu1 and selective mGlu5 antagonists, in a rat model useful to detect activity on the lower urinary tract. Surprisingly, good activity was found for antagonists selective for the mGlu5 receptor, whereas two commercially available antagonists selective for mGlu1 receptor failed to exhibit an effect. An antagonist selective for Group II mGluR receptors also failed to exhibit an effect in the rat model. Given these results, selective mGlu5 antagonists can be an effective means to treat lower urinary tract disorders.
There is a need in the art to develop novel compounds and compositions for the treatment of lower urinary tract disorders and for the alleviation of the symptoms associated with such disorders. The present inventors have addressed this need through the development of novel heterocyclic compounds that are selective mGlu5 modulators, including selective mGlu5 antagonists. The compounds of the present invention provide potent inhibition of the micturition reflex through a novel mechanism of action.